This application is related to U.S. Provisional Application Ser. No. 60/131,764 filed Apr. 30, 1999, which is incorporated herein by reference.
CD28 is a cell surface glycoprotein constitutively expressed on most mature T-cells and thymocytes, while the CTLA-4 receptor is not present on resting T cells and is only detectable 48 to 72 hours after T cell activation. The principal ligands for CD28/CTLA-4 molecules are B7.1 (CD80) and B7.2 (CD86) expressed on the surface of professional antigen presenting cells (APC). The biological rationale for the existence of at least two receptors (CD28 and CTLA-4) and two ligands (CD80 and CD86) is not clear. It was initially demonstrated that CD80 and CD86 antigens were functionally similar. However, different roles for these co-stimulatory molecules were first suggested when the different patterns of their expression were determined. CD86 is constitutively expressed on APC and after activation of APC, the expression of CD86 is quickly up-regulated followed by a gradual return to baseline levels. The expression of CD80 is delayed compared to CD86 and its expression is maximal 48 to 72 hours after the initiation of an immune response. Because CD86 expressed constitutively and up-regulated earlier than CD80 it was suggested that CD86 expression is important for the early phase of an immune response, while CD80 is important for the second.
Functional differences between CD80 and CD86 are further suggested by data on the binding kinetics of co-stimulatory molecules with CD28 and CTLA-4. Surface plasmon resonance (SPR) analysis has demonstrated that both ligands bind to CTLA-4 with higher avidity than to CD28. Further measurements revealed that the CD86/CTLA-4 complex dissociates faster than the CD80/CTLA-4 complex. These binding differences combined with the similar delay in expression of CTLA-4 and CD80 suggest that functional relationship between CTLA-4 and CD80 is probably more potent than functional relationship between CTLA-4 and CD86 molecules.
Multiple functions for CD80 and CD86 molecules in vitro and in vivo have been also reported. Anti-CD86 but not anti-CD80 antibodies block the development of disease in a mouse model of autoimmune diabetes, whereas the opposite effect is seen with these antibodies in a murine model of experimental allergic encephalomyelitis. Several experimental systems demonstrate an important role for CD86 in initiating a T-cell response to antigen and that the CD80 molecule may play an important role in providing modulatory signals to these cells. It was observed that expression of exogenous human CD86, but not CD80, provides important activation signals to murine T cells following DNA vaccination with envelope proteins from HIV-1. Similar results were observed after immunization of mice with DNA encoding HIV-1 or influenza antigens and plasmids encoding murine CD80 and CD86. Thus, functional differences between CD80 and CD86 were not connected with differential immunogenicity of human costimulatory molecules expressed in the mouse organism. It is believed that exogenous human or murine CD86, but not CD80, stimulates anti-viral T-cell activation during DNA immunization.
Vaccines are useful to immunize individuals against target antigens such as pathogen antigens or antigens associated with cells involved in human diseases. Antigens associated with cells involved in human diseases include cancer-associated tumor antigens and antigens associated with cells involved in autoimmune diseases.
In designing such vaccines, it has been recognized that vaccines which produce the target antigen in the cell of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use avirulent vectors and DNA vaccines all lead to the production of antigens in the cell of the vaccinated individual which results induction of the cellular arm of the immune system. On the other hand, sub-unit vaccines, which comprise only proteins, and killed or inactivated vaccines induce humoral responses but do not induce good cellular immune responses.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines which produce the target antigen in the cell of the vaccinated individual such as live attenuated vaccines, recombinant vaccines which use avirulent vectors and DNA vaccines are often preferred.
While such vaccines are often effective to immunize individuals prophylactically or therapeutically against pathogen infection or human diseases, there is a need for improved vaccines. There is a need for compositions and methods which produce an enhanced immune response.
Gene therapy, in contrast to immunization, uses nucleic acid molecules that encode non-immunogenic proteins whose expression confers a therapeutic benefit to an individual to whom the nucleic acid molecules are administered. A specific type of gene therapy relates to the delivery of genetic material which encodes non-immunogenic proteins that modulate immune responses in the individual and thus confer a therapeutic benefit. For example, protocols can be designed to deliver genetic material which encodes non-immunogenic proteins that downregulate immune responses associated with an autoimmune disease in an individual and thus confer a therapeutic benefit to the individual. There is a need for compositions and methods which can be used in gene therapy protocols to modulate immune responses.
Modulation of immune responses by alternative means is similarly desirable to treat diseases such as autoimmune disease and cell/tissue/organ rejection. There is a need for compositions and methods which can be used to modulate immune responses and to design and discover compositions useful to modulate immune responses.